2013

2013 Annual Scientific Meeting of the InterLymph Consortium

The International Lymphoma Epidemiology (InterLymph) Consortium is an open scientific forum for research in non-Hodgkin lymphoma and Hodgkin lymphoma. Established in 2001, the Consortium is an international collaboration of scientists who have completed or have ongoing lymphoma studies. Consortium members undertake research projects that pool data across studies to better understand lymphoma risk factors and prognostic factors. The member scientists include a broad range of expertise and currently include epidemiologists, geneticists, pathologists, haematologists, oncologists, immunologists, biostatisticians, bioinformaticians, and occupational hygienists.

The 2013 Annual Scientific Meeting of the InterLymph Consortium was held June 24-26th in Dijon, France at the University of Dijon. The meeting was supported and sponsored by the Lymphoma Coalition, Faculté de Médecine de Dijon, Institut de Veille Sanitaire, Registre des hémopathies malignes de Côte d'Or, INSERM, Institut National du Cancer, Université de Bourgogne, Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS), l'Institut Bergonié, The Lymphoma Study Association (LYSA), Registre Régional des Hémopathies de Basse Normandie, and the City of Dijon, France. Over 100 delegates from North America, Canada, Europe, Israel and Australia met for a symposium to exchange recent discoveries, to discuss ongoing pooled analyses, review provisional results, and plan new initiatives. Since lymphoma is a heterogeneous group of haematological malignancies, International pooled analyses of data from several thousands of people with and without lymphoma are required to study factors associated with individual lymphoma subtypes.

The Consortium continues to make seminal advances in our understanding of the environmental, genetic, lifestyle, infectious, and immunological risk factors for lymphoma. Five new InterLymph pooled analyses were published in international peer-reviewed scientific journals since our last report, including several focused on genetic risk factors.

One genetic risk factor study was led by Susan Slager from the Mayo Clinic (United States of America). It used the latest high-throughput technology to test the DNA of 3,100 individuals with chronic lymphocytic leukemia/small lymphocytic lymphoma cases and 7,667 healthy controls in the largest meta-analysis for CLL/SLL to date from studies participating in InterLymph Genome-Wide Association Study (GWAS) Initiative. These analyses identified ten independent associated common genetic variants in nine new gene loci at 10q23.31 (ACTA2/FAS), 18q21.33 (BCL2), 11p15.5 (C11orf21), 4q25 (LEF1), 2q33.1 (CASP10/ CASP8), 9p21.3 (CDKN2B-AS1), 18q21.32 (PMAIP1), 15q15.1 (BMF), and 2p22.2 (QPCT), as well as an independent signal at an established locus (2q13, ACOXL). The analyses also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1) and 5p15.33 (TERT). In all, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism (Berndt S et al. Nat Gen. 2013).

In another genetic study led by Dr. Alexandra Nieters from the University Medical Center of Freiburg (Germany), a validation genotyping study of 67 single nucleotide polymorphisms within InterLymph was conducted. A meta-analysis was performed on data from 5,633 B-cell NHL cases and 7,034 controls from 8 InterLymph studies. Gene variations in the proapoptotic BCL2L11 gene was associated with an increased risk for B-cell NHL, with similar risk estimates for common B-cell subtypes. PRRC2A in the HLA complex class III region conferred a reduced risk of B-cell NHL. These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes. (Nieters et al., Blood. 2012;120(23);4645-8).

In the first gene-environment analyses of NHL risk factors within the InterLymph consortium, Dr. Todd Gibson of the U.S. National Cancer Institute (United States) evaluated the role of smoking and variation in the N-acetyltransferance 1 (NAT1) and 2 (NAT2) genes, and risk of NHL among 5,026 NHL cases and 4,630 controls who had information on both smoking and either gene. This analysis was conducted to try to determine whether inconsistent results regarding smoking and NHL risk could be due to genetic variation that impacts the metabolism of tobacco-derived carcinogens, such as substrates of the n-acetyltransferase enzymes NAT1 and NAT2. In this analysis, current smoking was associated with a significant 30% increased risk of follicular lymphoma, but not other NHL subtypes. The association also did not differ by NAT1 or NAT2 status. The results thus provide further evidence of smoking as a risk factor specific to follicular lymphoma, but indicate that this risk is not modulated by the examined gene variants. (Gibson TM et al. Cancer Causes Control. 2013;24(1):125-34).

In another study of cigarette smoking, risk was evaluated for Hodgkin lymphoma (HL) and HL subtypes within the InterLymph consortium. Led by Henrik Hjalgrim of the Statens Serum Institute (Denmark), this analysis included 12 case-control studies and evaluated the association between smoking and HL stratified by tumor histology and Epstein-Barr virus (EBV) status among 3,335 HL cases and 14,278 controls. Compared with never smokers, ever smokers had modest 10% increased risk of HL, which reflected associations with mixed cellularity HL and EBV-positive HL among current smokers, whereas no risk increase was observed for nodular sclerosis and EBV-negative HL. As with NHL, these results support the notion of etiologic heterogeneity between HL subtypes, highlighting the need for HL stratification in future studies. (Kamper-Jorgensen et al. Ann Oncol. 2013 [Epub])

Finally, a pooled analysis of self-reported history of infections and NHL risk was led by Nicolaus Becker of the German Cancer Research Center (Germany). This analysis included data from 17 case-control studies comprising 12,585 cases and 15,416 controls. Self-reported history of infectious mononucleosis was associated with a 20% increased risk of NHL whereas a self-reported history of measles or whooping cough was associated with an approximate 15% reduction in risk. Despite these singular associations, the overall results from this study find little clear evidence of an association between NHL risk and infections. (Becker N et al. Int J Cancer. 2012 131;10:2342-8.)

The Consortium is currently completing several large-scale and internationally unique initiatives. The Subtypes initiative, led by Lindsay Morton, Dennis Weisenberger, James Cerhan and Susan Slager, includes data on more than 20,000 individuals and will report on the environmental, occupational, and lifestyle factors associated with 11 non-Hodgkin lymphoma subtypes, including the more common subtypes such as diffuse large B-cell lymphoma and follicular lymphoma, and rarer subtypes such as mantel cell lymphoma and acute lymphocytic lymphoma. At the June meeting, final results and multivariate models from each of the 11 subtypes were presented and manuscript submissions are expected by the end of 2013.

The InterLymph Genome Wide Association Study (GWAS) Initiatve, led by Nathaniel Rothman and Stephen Chanock at the National Cancer Institute, includes several thousand participants from a number of case-control and cohort studies. With the manuscript on CLL/SLL already published, results for the remaining subtypes – DLBCL, follicular lymphoma, marginal zone lymphoma, and T-cell lymphomas – were presented. The results yield a number of novel genetic loci associated with lymphoma risk and publications of these results are expected by the end of 2013. Other on-going Consortium projects include a number of projects further exploring the interaction between environmental factors and genetic predisposition. Secondary studies using data from the GWAS are also anticipated to commence in the coming year.